Bipolar disorder (BD) is a debilitating mood disorder that affects 1-2% of the population worldwide. Lithium is highly effective in BD, but the neuropharmacological mechanisms that underlie the therapeutic response is unknown. Defining the cellular and molecular targets of lithium in the adult brain will be crucial to understanding te molecular pathogenesis of this major affective disorder. We have advanced the hypothesis that lithium acts on mammalian behavior and mood disorders through inhibition of glycogen synthase kinase-3 (GSK-3), a central regulator of multiple signaling pathways. The goals of the work proposed here are to establish how cellular and molecular responses to GSK-3 inhibition relate to the therapeutic response in BD, with a long-term goal to understand the molecular basis of affective disorders and to discover new therapeutic targets in BD and other affective disorders. This proposal describes experiments to define the signaling mechanisms that account for the effects of lithium on neural stem cell homeostasis and behavior. Our working hypothesis is that GSK-3 modulates both behavior and neurogenesis through interaction with Wnt signaling and oxygen sensing pathways. In addition, we hypothesize that GSK-3 is highly regulated by positive feedback circuits that can be targeted for the development of new therapeutic strategies in affective disorders. In aim 1, we will test whether Wnt signaling is required for neurogenic or behavioral responses to lithium. We will also test whether neurogenesis is required for behavioral responses to lithium using a genetic strategy to target NSPCs in the adult hippocampus. Aim 2 addresses a newly uncovered connection between oxygen sensing (through hypoxia inducible factor-1) and the Wnt pathway, a major target of GSK-3 and a regulator of neurogenesis. We will explore the role of HIF-1 in the regulation of neurogenesis and lithium-sensitive behaviors and investigate the role of HIF-1 target genes in the response to lithium. In aim 3 we will explore a novel mechanism that regulates the sensitivity of GSK-3 to inhibition by lithium or by endogenous signals involved in the control of mood. We will investigate approaches to perturb these GSK-3 regulatory circuits as potentially new therapeutic targets in the treatment of bipolar disorder and other affective disorders. These studies should provide a better understanding of the molecular and cellular mechanisms that underlie BD and the response to therapy and should lead to new approaches to the treatment of this common and devastating affective disorder.